ABSTRACT

Context The risk of acquiring babesiosis by blood transfusion
is largely unknown since in areas where it is endemic it is often an
asymptomatic infection.

Objective To investigate and treat a cluster of blood
transfusion–associated babesiosis cases.

Design Case series and epidemiologic investigation.

Setting Urban inner-city hospital.

Patients Six persons who received Babesia
microti–infected blood components from a donor.

Main Outcome Measure Diagnosis and successful therapy of
babesiosis following transfusion.

Results Six individuals (1 adult, 1 child, and 4 neonates) were
exposed to products from a single blood donation by an asymptomatic
Babesia-infected donor. Three of the 6 exposed patients became
parasitemic. Polymerase chain reaction testing, animal inoculation
studies, and indirect immunofluorescent antibody testing were used to
confirm the presence of Babesia microti in the donor's blood
and to establish the presence of infection in 3 of the 6 recipients.
The 3 infected recipients and 1 additional recipient were treated
without incident.

Conclusion Physicians should consider babesiosis in the
differential diagnosis of a febrile hemolytic disorder after blood
transfusion. Prompt diagnosis is important since babesiosis is
responsive to antibiotic therapy and, untreated, can be a fatal disease
in certain risk groups.

Babesiosis is a tick-borne disease of animals that occasionally occurs in humans. In
the United States, most cases of babesiosis occur in the Northeast and
are caused by the rodent parasite Babesia microti, an
intraerythrocytic protozoan transmitted by the northern deer tick,
Ixodes dammini.1 Babesiosis is prevalent in the
coastal areas and islands of New England and New York. More recently,
cases of babesiosis caused by various Babesia species have
been reported from California, Washington, Missouri, Wisconsin, and
Minnesota.2 Evidence suggests that because most B
microti infections are asymptomatic or are not diagnosed for other
reasons, Babesia infection is more common than the several
hundred reported tick-borne cases would suggest.3 The
clinical manifestations of babesiosis vary from asymptomatic infection
to severe and sometimes fatal disease characterized by fever,
hemolytic anemia, hemoglobinuria, and renal failure.2
Asplenic individuals and patients with underlying immunodeficiency, eg,
elderly patients or patients with acquired immunodeficiency syndrome,
are particularly susceptible to severe manifestations.4,5

Because asymptomatic parasitemia can be prolonged for months to
years,6 and the parasite can remain infective under
blood-banking conditions,7 transmission of Babesia
is a risk of blood transfusion. The blood components that have been
implicated in transfusion
babesiosis include liquid-stored erythrocytes,
frozen-deglycerolized red cells, and platelet concentrates, which
usually contain residual erythrocytes.8 With the
substantial increase in the white-tailed deer population (the preferred
host for the adult tick) and the widening range of the tick
vector,1 an increase in the incidence of babesiosis and
transfusion-transmitted infections is possible.

We describe a cluster of cases of transfusion-transmitted babesiosis.
Six persons were exposed to components from a single blood donation by
an asymptomatic Babesia-infected donor and 3 became
demonstrably parasitemic.

METHODS

At least 300 thin-smear fields were examined at a magnification of
1000. If no parasites were identified, at least 300 thick-smear fields
were examined at a magnification of 1000.

Serum specimens were tested at the Centers for Disease Control and
Prevention, Atlanta, Ga, by indirect immunofluorescent antibody (IFA)
assay for reactivity to B microti.

At the Centers for Disease Control and Prevention, anticoagulated blood
(0.2-1.0 mL) from the donor and recipients was inoculated
intraperitoneally into golden hamsters. Giemsa-stained blood from tail
vein snips was examined weekly for 8 weeks for parasitemia.

Blood from the donor and recipients was examined using polymerase chain
reaction (PCR) for parasite DNA. The primers used were Bab1
(5′-CTTAGTATAAGCTTTTATACAGC-3′) and Bab4
(5′-ATAGGTCAGAAACTTGAATGATACA-3′).9 Parasite DNA was
extracted from blood using the XTRAX Kit (Gull Laboratories, Salt Lake
City, Utah).

CASE REPORTS

The index case (patient 1) was a 44-day-old, full-term male
infant who was ventilator dependent and had been hospitalized for his
entire life. On the 22nd day of life, he was transfused with 20
mL/kg (60 mL) of packed red blood cells because his hematocrit
was 0.27. He had received no other transfusions. Twenty-two days later
he became febrile (temperature, 39°C). Total white blood cell count
was 24.0 × 109/L with 13.2 × 109/L
neutrophils, 0.24 × 109/L band forms, 7.7 ×
109/L lymphocytes, and 2.9 × 109/L
monocytes; hematocrit was 0.35 and platelet count was
8.8 × 109/L. Examination of the peripheral smear
revealed intraerythrocytic ring forms, consistent with either
Plasmodium or B microti with an estimated 1%
parasitemia. The diagnosis of babesiosis was confirmed by the presence
of pathognomonic intraerythrocytic tetrad forms and by PCR results that
were positive for B microti DNA.

Therapy with oral quinine sulfate (25 mg/kg per day) and intravenous
clindamycin phosphate (20 mg/kg per day) was initiated. He remained
febrile for the first 4 days of therapy, the parasitemia increased to
8%, and the hematocrit fell to
0.31. On day 5, the quinine dosage was increased
to 30 mg/kg per day, clindamycin therapy was continued, and atovaquone
therapy, 45 mg/kg per day, was added. The following day, the
parasitemia fell to less than 3% and the fever subsided. By the fourth
day following the addition of atovaquone therapy, no parasites were
seen on blood smears. The findings of daily smears for the next 2 weeks
were consistently negative for parasites; PCR done 3 weeks following
treatment was also negative for Babesia DNA. The infant's
pretreatment serum had no antibody to malaria but showed a rising titer
to B microti antigen (Table 1). The infant's mother had not
traveled outside the New York City metropolitan area, and had never
received a blood transfusion. No parasites were seen in her blood
smear, and her IFA titer to B microti antigen was 1:8 or
lower.

Table Graphic Jump LocationTable. Summary of the Diagnosis, Treatment, and Outcome of the Patients Transfused With Babesia microti–Infected Blood*

The donor was a resident of Suffolk County (Long Island), New York, an
area where babesiosis is endemic. During the fall of 1996, he had taken
3 hunting trips near his home. He did not recall finding ticks on his
body. An interview with the donor when he donated blood (January 1997)
was unremarkable; he had remained well thereafter. No parasites were
seen when his blood smear was examined on postdonation day 45, but his
IFA titer to B microti antigen was 1:1024. Untransfused
cryoprecipitate from the implicated donation had an IFA titer of
1:1024. In addition, a smear of blood obtained from the remnant
(tubing) sample of the implicated packed red blood cell unit showed a
single ring form consistent with B microti, and the PCR
results were positive for B microti DNA. A hamster inoculated
with blood from the donor (postdonation day 45) did not become
parasitemic. The donor's antibody titer as measured by enzyme-linked
immunosorbent assay to Borrelia burgdorferi antigen was
negative.

Five additional individuals were identified as having received portions
of the implicated blood donation and were evaluated for babesiosis.
Three premature neonates received packed red blood cells (20
mL/kg; volume ranged from 16 to 40 mL); a 70-year-old woman with
a history of thalassemia and gastrointestinal bleeding was transfused
with 220 mL of packed red blood cells; and an 11-year-old boy receiving
chemotherapy was transfused with platelets from the implicated
donation. The evaluations and outcomes of these 5 patients are
summarized in Table 1.

Two additional recipients besides the index case became infected, but
neither showed signs of clinical illness. All recipients were tested
for antibody to B microti, had blood smears examined daily,
and had blood inoculated into hamsters. On the 11th day of daily
monitoring (posttransfusion day 40), patient 2 was afebrile but had
positive blood smear results with less than 1% parasitemia and
positive PCR results. Treatment with oral atovaquone, 40 mg/kg per day,
and oral azithromycin, 12 mg/kg per day, was given for 7 days. The
regimen was well tolerated and results of smears became negative on the
fourth treatment day. Hamsters inoculated with blood drawn on the fifth
treatment day became parasitemic; inoculation of hamsters with blood
obtained 8 weeks after completion of therapy failed to demonstrate
parasitemia and the PCR results were negative. Serological test results
showed a rise in B microti antibody titer. The infant was
monitored after discharge and was healthy and thriving at age 1 year.
All test results, including daily blood smears, remained negative for
patients 3 and 4 (Table 1) Patient 3 was treated prophylactically with
atovaquone and azithromycin.

The adult recipient, patient 5, had a blood smear with a 3%
parasitemia (posttransfusion day 28). The results of serological
testing, PCR analysis, and hamster inoculation were positive (Table 1
). Although afebrile and asymptomatic, she was treated with a 7-day course
of oral quinine (650 mg 3 times daily) and oral clindamycin (10 mg/kg 3
times daily). No parasites were seen in her blood smear on the fifth
day of therapy. She has remained asymptomatic and blood smears and PCR
results have remained negative. Patient 6, who received platelets,
remained asymptomatic, and no parasites were ever detected in his blood
smear; IFA titer and hamster inoculation were negative.

COMMENT

This is the first report of transmission of B microti to
multiple recipients of a single contaminated blood unit and only the
second of transfusion-acquired babesiosis in the neonatal
host.10 The risk for transmission of B microti
infection via contaminated blood components has been recognized since
the late 1970s. However, direct measures of risk are not available and
estimates of the likelihood of acquiring Babesia from a unit
of blood are based on reported cases or seroepidemiologic studies.
Including those in the present report, more than 20 cases of
posttransfusion babesiosis have been reported. Since the number of
blood units donated each year in the United States is approximately 12
million, the annual incidence of recognized posttransfusion babesiosis
has been less than 1 per 1 million units of donated
blood.11,12 However, the risk of transmission by blood
components may vary by region. For example, in a study of surgical
patients from Connecticut, a state in which 2% to 4% of some
outpatient populations have been found to be seropositive,3
the risk of acquiring Babesia infection was 0.17% (1/601) per
unit of packed cells.13

Although B microti is the second most commonly reported cause
of transfusion-acquired parasitic infection,14 testing of
all blood donors for evidence of past or present B microti
infection has not been considered practical; neither is screening of
high-risk donors based on residence or tick exposure.15,16
In the United States, blood banks do not routinely ask blood donors
about recent tick bites, although donors who report a history of
babesiosis are deferred.3 However, since most infections
with B microti are subclinical and, therefore, undiagnosed,
the question "Have you ever had babesiosis?" will not identify most
donors with past or present infection.

Currently, the IFA test is the serologic test of choice for the
detection of B microti antibody. This test is reliable,
although time consuming, labor intensive, and
subject to qualitative interpretation, and it does
not lend itself to mass screening. Similarly, PCR testing is not
generally available, and its utility for large-scale testing for
babesiosis is unknown. Thus, better screening tools are needed as well
as better assessment of the risk babesiosis poses to the blood supply.

All of the previously reported cases of transfusion-acquired
babesiosis were in patients who became moderately to severely ill from
their infections. In adults, the most severe and occasionally fatal
cases of babesiosis (both tick- and transfusion-acquired) have occurred
in splenectomized and other immunocompromised
individuals.4,5,17 The presence of Howell-Jolly and Heinz
bodies in the peripheral circulation of newborns has raised questions
about the phagocytic capacity of the spleens of newborns.18
The phagocytic activity of the spleen has been demonstrated to have a
critical role in the clearance of B microti in the golden
hamster model.19 Studies of phagocytic function in the
newborn rat have indicated that although splenic phagocytic activity
was significantly impaired at birth, it rapidly increased to adult
levels during the first 2 weeks of life.20 Rapid maturation
of splenic function may explain why infected infants do not uniformly
succumb to overwhelming Babesia infection. Cellular immunity
also seems to be important for resistance to and recovery from
babesiosis, as indicated by studies in nude mice.21 The
increased susceptibility of newborn mice to severe infection with other
intracellular pathogens suggests that neonates also might have impaired
ability to clear B microti, even with a functional
spleen.22 These considerations prompted the aggressive
therapeutic as well as prophylactic approach in the management of
babesiosis in the infected and exposed newborns.

Quinine and clindamycin, standard therapy for babesiosis, were
initially used for the treatment of patient 1. However, because of the
persistent and rising parasitemia, atovaquone therapy was added on the
fourth day of treatment. The parasitemia resolved by the fourth day of
combined quinine, clindamycin, and atovaquone therapy. The use of
atovaquone was prompted by 2 recent studies demonstrating the efficacy
of atovaquone in the hamster model.23,24 When used as
monotherapy, atovaquone was found to be effective for both treatment
and prophylaxis. However, other studies have shown that with
monotherapy, recrudescence and development of high-grade resistance
appeared, which were not encountered with the atovaquone-azithromycin
combination.23 Atovaquone and azithromycin were selected
for the therapy and prophylaxis, respectively of patients 2 and 3 and
were well tolerated in both cases. This adds to the growing anecdotal
experience for the use of atovaquone and azithromycin in human cases of
B microti infections.23,25

Physicians, especially in areas where the disease is endemic, should
consider babesiosis in the differential diagnosis of a febrile
hemolytic disorder after blood transfusion. Prompt diagnosis is
important because babesiosis is amenable to antibiotic therapy and
untreated, in certain risk groups, can be a fatal disease.

Letters

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